Synthesis of some novel quinoline-3-carboxylic acids and pyrimidoquinoline derivatives as potential antimicrobial agents

Article abstract of DOI:10.1002/1521-4184(200212)335:9<403::AID-ARDP403>3.0.CO;2-9

The synthesis and in vitro antimicrobial evaluation of several quinoline and pyrimidoquinoline derivatives are described. Treatment of 7-substituted quinolin-2(1H)-one-3-carboxylic acids 2 a-c with phosphoryl chloride or thionyl chloride gave rise to the 7-substituted 2-chloroquinoline-3-carboxylic acids 3 a-c and 7-substituted 2-chloro-3-chlorocarbonylquinolines 5 a-c respectively. The 2-chloro function in compounds 3 a-c was replaced by 2-aminothiazole or 2-aminopyridine to give 2-(thiazol-2-yl)aminoquinoline-3-carboxylic acids 4 a-c or 2-(pyrid-2-yl)aminoquinoline-3-carboxylic acids 4 d-f. Treatment of 5 a-c with the same heterocyclic amines at room temperature furnished the corresponding 7-substituted 2-chloro-3-heteryl- aminocarbonylquinolines 6a-f. The tetracyclic 9-substituted thiazolo[3′,2′: 1,2]-pyrimido[4,5-b]quinolin-5-ones 7a-c and 10-substituted pyrido[1′,2′: 1,2]- pyrimido[4,5-b]quinolin-6-ones 7 d-f were synthesized by heating 5 a-c with the heterocyclic amines in toluene or by heating 6 a-f under reflux in dimethylformamide. The products were evaluated in vitro for potential antimicrobial activity.

Full text of DOI:10.1002/1521-4184(200212)335:9<403::AID-ARDP403>3.0.CO;2-9

Arch. Pharm. Pharm. Med. Chem. 2002, 9, 403–410
Potential Antimicrobial Agents 403
Ola A. El-Sayeda,
Synthesis of Some Novel Quinoline-3-carboxylic
Acids and Pyrimidoquinoline Derivatives as
Potential Antimicrobial Agents
Badr A. Al-Bassamb,
Maher E. Husseinc
a
Pharmaceutical Chemistry
Department,
The synthesis and in vitro antimicrobial evaluation of several quinoline and pyrimido-
quinoline derivatives are described.Treatment of 7-substituted quinolin-2(1H)-one-
3-carboxylic acids 2 a–c with phosphoryl chloride or thionyl chloride gave rise to the
7-substituted 2-chloroquinoline-3-carboxylic acids 3 a–c and 7-substituted 2-chlo-
ro-3-chlorocarbonylquinolines 5 a–c respectively. The 2-chloro function in com-
pounds 3 a–c was replaced by 2-aminothiazole or 2-aminopyridine to give 2-(thi-
azol-2-yl)aminoquinoline-3-carboxylic acids 4 a–c or 2-(pyrid-2-yl)aminoquinoline-
3-carboxylic acids 4 d–f. Treatment of 5 a–c with the same heterocyclic amines at
room temperature furnished the corresponding 7-substituted 2-chloro-3-heteryl-
aminocarbonylquinolines 6 a–f. The tetracyclic 9-substituted thiazolo[3Ј,2Ј:1,2]-
pyrimido[4,5-b]quinolin-5-ones 7 a–c and 10-substituted pyrido[1Ј,2Ј:1,2]-
pyrimido[4,5-b]quinolin-6-ones 7 d–f were synthesized by heating 5 a–c with the
heterocyclic amines in toluene or by heating 6 a–f under reflux in dimethylform-
amide. The products were evaluated in vitro for potential antimicrobial activity.
Faculty of Pharmacy,
University of Alexandria,
Alexandria, Egypt
Biochemistry Department,
Botany & Microbiology
b
c
Department,
College of Science,
King Saud University,
Riyadh, Saudi Arabia
Keywords: Quinoline-3-carboxylic acids; Pyrimidoquinolines; Antimicrobial
Received: August 21, 2001 [FP624]
2-position 4 a–f and then included within a fused poly-
heterocyclic structure of thiazolopyrimidoquinolin-5-
Introduction
The search for new antimicrobial drugs is an area char-
acterized by active investigation with the goal of over-
coming the phenomenon of multiple drug resistance. It
is well-known that the quinoline nucleus and its deriva-
tives, particularly quinolones, play a vital role in the de-
sign of an important class of wide spectrum antibacteri-
al agents. Structure-activity relationship (SAR) studies
revealed that the antimicrobial activity in this class of
compounds depends on the nature of the peripheral
substituents and their spatial relationship [1–7] within
the quinoline nucleus. Moreover, substitution in 6- or 7-
position as well as the presence of N-ethyl or cyclohexyl
groups [8, 9] are requisites for enhancing antibacterial
activity in the quinoline series. The 4-hydroxyquinoline-
3-carboxamides [10] have also been reported to pos-
sess antiviral activity. In the present study, several quin-
oline derivatives have been designed which bear a sim-
ple alkyl or alkoxyl group in the 7-position while a free
carboxylic 3 a–c or carboxamide function 6 a–f is locat-
ed in the 3-position. Also, a 2-amino(1,3)thiazole or
2-aminopyridine moiety has been located in the
ones 7 a–c and pyridopyrimidoquinolin-6-ones 7 d–f.
The study has the aim of evaluating which structural
modification of quinoline would potentiate the antimicro-
bial activity of such a new type of compounds.
Results and discussion
Chemistry
The synthesis of the designed compounds was achieved
following the routes depicted in Scheme 1.Hydrolysis of
1 a–c [11, 12] with H2SO4 (70 %) gave the 7-substituted
quinolin-2(1H)-one-3-carboxylic acids 2 a–c in good
yields.Heating 2 a–c in boiling phosphoryl chloride gave
the 7-substituted 2-chloroquinoline-3-carboxylic acids
3 a–c. The latter compounds were allowed to react with
the selected heterocyclic amines, viz 2-amino-1,3-thi-
azole and 2-aminopyridine, in dimethylformamide con-
taining few drops of triethylamine to give the correspond-
ing 7-substituted 2-(1,3-thiazol-2-yl)aminoquinoline-3-
carboxylic acids 4 a–c and 2-(pyrid-2-yl)aminoquinoline-
3-carboxylic acids 4 d–f. On the other hand, heating
2 a–c with thionyl chloride gave the 2-chloroquinoline-3-
carbonyl chloride derivatives 5 a–c which were pure
Correspondence:
Ola
A. El-Sayed,
Pharmaceutical
Chemistry Department, Faculty of Pharmacy, University of
Alexandria, Alexandria 21215, Egypt.Phone:+20 03 487 1317,
Fax: +20 03 487 3273, e-mail: oolaomar@hotmail.com.

404 El-Sayed et al.
Arch. Pharm. Pharm. Med. Chem. 2002, 335, 403–410
Scheme 1
enough (TLC) for use in subsequent steps. These acyl
chlorides 5 a–c were stirred at room temperature with
2-amino(1,3)thiazole or 2-aminopyridine in toluene con-
taining few drops of pyridine to give the respective 7-sub-
stituted 3-(1,3-thiazol-2-yl)aminocarbonyl-2-chloroqui-
nolines 6 a–c or 3-(pyrid-2-yl)aminocarbonyl-2-chloro-
quinolines 6 d–f. Conversion of these acid amides 6 a–f
into 9-substituted thiazolo[3Ј,2Ј:1,2]pyrimido[4,5-b]-
quinolin-5-ones 7 a–c and 10-substituted pyrido-
[1Ј,2Ј:1,2]pyrimido[4,5-b]quinolin-6-ones 7 d–f were ef-
fected by heating under reflux in dimethylformamide with
2-amino(1,3)thiazole and 2-aminopyridine respectively.
Also, compounds 7 a–c and 7 d–f were synthesized
through a one-pot reaction by heating 5 a–c with 2-
amino(1,3)thiazole or 2-aminopyridine under reflux in
toluene.Elemental analyses and spectral data assessed
the structure of the products.
Gram-positive and three Gram-negative bacteria, and
two fungi. Ampicillin and clotrimazole were used as con-
trol.
The minimum inhibitory concentrations (MICs, µg/mL)
for all tested compounds were determined by a standard
two-fold serial dilution method using agar media [13].
The results, as collectively recorded inTable 1, indicated
that 2-chloroquinoline-3-carboxylic acid 3a was active
against Staphylococcus aureus and Candida albicans.
The 7-methyl analog 3 b was highly active against Bacil-
lus thuringiensis and Bacillus anthracis but was devoid of
antifungal activity. The 7-methoxy derivative 3 c exerted
strong antibacterial and antifungal activities against Ba-
cillus anthracis and Candida albicans respectively.Com-
pounds 4, having a 2-amino-1,3-thiazole 4 a–c or 2-ami-
nopyridine moiety 4 d–f in place of the chloro function at
the 2-position of 3 a–c, displayed excellent antibacterial
activity against Bacillus anthracis.
Antimicrobial activity
The pyridine-containing compounds were the most ac-
tive, especially when a methoxyl group was located in
the 7-position of quinoline nucleus.Thus the 7-methoxy-
The antimicrobial activity of the synthesized compounds
was evaluated in vitro against an assortment of five

Arch. Pharm. Pharm. Med. Chem. 2002, 335, 403–410
Potential Antimicrobial Agents 405

406 El-Sayed et al.
Arch. Pharm. Pharm. Med. Chem. 2002, 335, 403–410
filtered while hot and the filtrate acidified with dilute H2SO4.The
separated product was filtered and crystallized from ethanol.IR
(cm–1): 3413–3227 (br. NH and OH), 1675–1665 (C=O). 13C-
NMR for quinolin-2(1H)-one-3-carboxylic acid 2 a: 162.74
(COOH), 162.19 (C2), 144.58 (C8a), 137.59 (C3), 132.05 (C4),
128.39 (C4a), 121.97 (C5), 117.34 (C7), 115.63 (C6), 114.37
(C8). Physical and spectral data of the products are recorded in
Table 2.
2-(1,3-thiazol-2-yl)aminoquinoline-3-carboxylic acid 4 c
was the only compound among the thiazole-containing
derivatives to show potent antibacterial activity. Conver-
sion of the 3-carboxylic group into a carboxamide func-
tion imparted a distinct activity to the products 6 a–f
against Candida albicans. Their antibacterial testing re-
vealed a potent activity for 7-methoxy-3-(1,3-thiazol-2-
yl)aminocarbonyl-2-chloroquinoline 6c against Staphy-
lococcus aureus, Bacillus anthracis, Escherichia coli
ATCC 25722, and Candida albicans.
7-Substituted 2-chloroquinoline-3-carboxylic acids 3 a–c
A mixture of the appropriate 7-substituted quinolin-2(1H)-one-
3-carboxylic acids 2 a–c (0.01 mol) and excess phosphoryl
chloride (10 mL) was heated under reflux for 2 h.The reaction
mixture was left to attain room temperature and then poured in-
to ice-cold water. The separated product was filtered, washed
with water and crystallized from dimethylformamide/ethanol
(1 : 1).IR (cm–1):3313–2700 (br.OH), 1700–1685 (C=O).Physi-
cal and spectral data of the products are recorded in Table 2.
On the other hand, most of the fused polynuclear prod-
ucts, thiazolopyrimidoquinolin-5-one 7 a–c and pyri-
dopyrimidoquinolin-6-one 7 d–f derivatives exerted a
potent antifungal activity against Aspergillus flavus and
Candida albicans in addition to a pronounced antibacte-
rial activity against Bacillus thuringiensis.
7-Substituted 2-(1,3-thiazol-2-yl/pyrid-2-yl)aminoquinoline-3-
carboxylic acids 4 a–f
Summing up the results, the location of a methoxyl group
in the 7-position of the quinoline nucleus enhanced the
antibacterial activity more than the methyl group. Also,
the presence of a free carboxylic group as a C3-substitu-
ent was essential for the antibacterial acitivity, as always
revealed by SAR studies of active quinolones [8].Mean-
while, changing the spatial arrangement by embedding
the C=O of the carboxylic or carboxamide function into
pyrimidine ring fused to the quinoline nucleus and in-
cluding the N-1 ethenyl or butadienyl moiety within thia-
zole 7 a–c or pyridine ring system 7 d–f respectively led
to enhancement of the antifungal activity over the anti-
bacterial effect.
A solution of 3 a–c (0.01 mol) in dimethylformamide (10 mL)
was treated with the equivalent amount of the selected hetero-
cyclic amine and few drops of triethylamine. The reaction mix-
ture was heated under reflux for 6–8 h, concentrated, cooled,
and then poured onto cold water (30 mL).The separated prod-
uct was filtered off and crystallized from ethanol. IR (cm–1):
3341–2800 (NH, br. OH), 1730–1725 (C=O). Physical and
spectral data of the products are recorded in Table 3.
7-Substituted 2-chloroquinoline-3-carbonylchlorides 5 a–c
A well-stirred suspension of 2 a–c or 3 a–c (55 mmol) in thionyl
chloride (25 mL) was heated under reflux for 1.5 h. Excess
thionyl chloride was removed in vacuo and the residual materi-
al was repeatedly treated with small portions of benzene and
evaporated in vacuo until all thionyl chloride was removed.The
residual solid was used without further purification. IR (cm–1):
1760 (C=O).
7-Substituted 3-(1,3-thiazol-2-yl/pyrid-2-yl)aminocarbonyl-2-
chloroquinolines 6 a–f
Experimental
Chemistry
A suspension of 5 a–c (0.01 mol) in toluene (5 mL) was treated
with the appropriate heterocyclic amine (0.01 mol) and few
drops of pyridine.The reaction mixture was stirred at room tem-
perature for 1 h and the solvent was then removed in vacuo.
The formed product was crystallized from dimethylformamide/
ethanol (1 : 2). IR (cm–1): 3250 (NH), 1635–1630 (C=O). The
physical and spectral data of the products are reported in
Table 3.
Melting points were determined in open glass capillaries and
are uncorrected. IR spectra (KBr discs) were recorded on a
Perkin Elmer 1430 spectrometer. 1H-NMR and 13C-NMR were
recorded on Jeol-NMR 400 MHz spectrometer in DMSO-d6 us-
ingTMS as internal standard.The chemical shifts are given in δ
(ppm) values. Microanalyses were performed on Perkin-Elmer
2400 elemental analyzer, at the Central Laboratory of the Col-
lege of Pharmacy, King Saud Universiy and were satisfactory
within ± 0.4 % of the calculated values.
9-Substituted thiazolo[3Ј,2Ј:1,2]pyrimido[4,5-b]quinolin-5-
ones 7 a–c and 10-Substituted pyrido[1Ј,2Ј:1,2]pyrimido-
[4,5-b]quinolin-6-ones 7 d–f
7-Methoxyquinolin-2(1H)-one-3-carbonitrile 1 c
This compound was prepared as previously reported [12]
starting from 7-methoxy-2-chloroquinoline-3-carboxaldehyde
[14], yield (75 %), mp >300 °C. Analysis: C11H8N2O2 (MW =
200.19). IR (cm–1): 3335 (NH), 2230 (C≡ N), 1665 (C=O). 1H-
NMR: 3.52 (s, 3 H, OCH3), 7.28 (d, J = 8.8 Hz, 1 H, C6-H), 7.57
(s, 1 H, C8-H), 7.88 (d, J = 8.8 Hz, 1 H, C5-H), 8.20 (s, 1 H, C4-H),
11.2 (s, 1 H, NH, D2O- exchangeable).
Method A:
A solution of 6 a–f (0.01 mol) in dimethylformamide (10 mL)
was heated under reflux for 4 h. The reaction mixture was
cooled and poured onto ice-cold water.The formed precipitate
was filtered and crystallized from dimethylformamide/ethanol
(1 : 2).
7-Substituted quinolin-2(1H)-one-3-carboxylic acids 2 a–c
Method B:
A mixture of the appropriate 1 a–c (0.01 mol) and sulfuric acid
75 % (5 mL) was heated to about 150–160 °C for 2 h.The reac-
tion mixture was cooled, poured onto ice-cold water and fil-
tered.The crude material was dissolved in excess NaOH 10 %,
A suspension of 5 a–c (0.01 mol) in toluene (5 mL) was stirred
at room temperature and treated with an equimolar amount of
the appropriate amine added portionwise.The reaction mixture
was then heated under reflux for 1.5 h and cooled.The separat-

Arch. Pharm. Pharm. Med. Chem. 2002, 335, 403–410
Potential Antimicrobial Agents 407
1
Table 2. Physicochemical data and H-NMR of compounds 2 a–3 c.
Comp.
No.
R
H
Yield
[%]
Mp
[°C]
Mol. formula
(Mol. wt.)
1H-NMR
(DMSO-d6)
2 a
2 b
2 c
3 a
95
90
90
60
258–260
> 300
C10H7NO3
(189.17)
7.31 (dd, J = 7.32, 8.08 Hz, 1 H, C7-H), 7.52 (dd, J = 7.36,
8.08 Hz, 1 H, C6-H), 7.75 (d, J = 8.8 Hz, 1 H, C5-H), 8.06
(d, J = 8.8 Hz, 1 H, C8-H), 9.02 (s, 1 H, C4-H), 9.51, 12.62
(two s, 2 H, NH, OH, D2O-exchangeable).
CH3
OCH3
H
C11H9NO3
(203.19)
2.31 (s, 3 H, CH3), 7.58 (d, J = 8.8 Hz, 1 H, C6-H), 7.68 (d,
J = 8.8 Hz, 1 H, C5-H), 8.10 (s, 1 H, C8-H), 9.21 (s, 1 H,
C4-H), 9.43, 12.52 (two s, 2 H, NH, OH, D2O-exchange-
able).
> 300
C11H9NO4
(219.19)
3.42 (s, 3 H, OCH3), 7.77 (d, J = 8.8 Hz, 1 H, C6-H), 7.94
(d, J = 8.8 Hz, C5-H), 8.30 (s, 1 H, C8-H), 8.92 (s, 1 H,
C4-H), 10.1, 12.08 (two s, 2 H, NH, OH, D2O-exchange-
able).
218–220
C10H6ClNO2
(207.61)
7.51 (dd, J = 7.34, 8.80 Hz, 1 H, C7-H), 7.56 (dd, J = 7.36,
8.08 Hz, 1 H, C6-H), 7.58 (d, J = 8.8 Hz, 1 H, C5-H); 7.93
(d, J = 8.8 Hz, 1 H, C8-H), 8.20 (s, 1 H, C4-H), 8.91 (s, 1 H,
OH, D2O-exchangeable)
3 b
3 c
CH3
65
75
226–228
144–146
C11H8ClNO2
(221.64)
2.30 (s, 3 H, CH3), 7.52 (d, J = 8.8 Hz, 1 H, C6-H), 7.88 (d,
J = 8.06 Hz, 1 H, C5-H), 7.99 (s, 1 H, C8-H), 8.23 (s, 1H,
C4-H), 9.21 (s, 1 H, OH, D2O-exchangeable)
OCH3
C11H8ClNO3
(237.64)
3.52 (s, 3 H, OCH3), 7.48 (d, J = 8.8 Hz, 1 H, C6-H), 7.62
(d, J = 8.8 Hz, 1 H, C5-H), 7.68 (s, 1 H, C8-H), 8.32 (s, 1 H,
C4-H), 9.17 (s, 1 H, OH, D2O-exchangeable)
Table 3. Physicochemical data and 1H-NMR of compounds 4 a–f and 6 a–f.
Comp
No.
R
H
Ar
Yield
[%]
Mp
[°C]
Mol. formula
(Mol. wt.)
1H-NMR
(DMSO-d6)
4 a
2-thiazolyl
60
>300
C13H9N3O2S
(271.30)
6.91 (d, J = 4.14 Hz, 1 H, thiaz-C5-H), 7.21
(d, J = 4.4 Hz, 1 H, thiaz-C4-H), 7.79 (dd,
J = 7.32, 8.08 Hz, 1 H, quin-C7-H), 7.91 (dd,
J = 7.32, 8.08 Hz, 1 H, quin-C6-H), 8.21 (d,
J = 8.68 Hz,1 H, quin-C5-H), 8.68 (d,
J = 8.68 Hz, 1 H, quin-C8-H), 8.72 (s, 1 H,
quin-C4-H), 12.42, 13.41 (two s, 2 H, NH,
OH, D2O-exchangeable).
4 b
CH3
2-thiazolyl
70
224–226
C14H11N3O2S
(285.32)
2.34 (s, 3 H, CH3), 7.32 (d, J = 4.2 Hz, 1 H,
thiaz-C5-H), 7.46 (d, J = 4.2 Hz, 1 H, thiaz-
C4-H), 7.76 (d, J = 8.4 Hz, 1 H, quin-C6-H),
7.97 (d, J = 8.04 Hz, 1 H, quin-C5-H), 8.52
(s, 1 H, quin-C8-H), 8.71 (s, 1 H, quin-C4-H),
12.39, 13.14 (two s, 2 H, NH, OH, D2O-
exchangeable).

408 El-Sayed et al.
Arch. Pharm. Pharm. Med. Chem. 2002, 335, 403–410
Table 3. (continued)
Comp
No.
R
Ar
Yield
[%]
Mp
[°C]
Mol. formula
(Mol. wt.)
1H-NMR
(DMSO-d6)
4 c
OCH3
2-thiazolyl
50
224–226
C14H11N3O3S
(301.32)
3.45 (s, 3 H, OCH3), 7.33 (d, J = 4.16 Hz,
1 H, thiaz-C5-H), 7.64 (d, J = 4.1 Hz, 1 H,
thiaz-C4-H), 7.78 (d, J = 8.06 Hz, 1 H, quin-
C6-H), 7.97 (d, J = 8.06 Hz, 1 H, quin-C5-H),
8.54 (s, 1 H, quin-C8-H), 8.67 (s, 1 H, quin-
C4-H), 12.34, 13.24 (two s, 2 H, NH, OH,
D2O-exchangeable)
4 d
H
2-pyridyl
58
265–267
C15H11N3O2
(265.27)
7.23, 7.31 (two dd, J = 5.21, 7.02 Hz, 2 H,
pyrid-C4,5-H), 7.40 (d, J = 5.21 Hz, 1 H,
pyrid-C3-H), 7.42 (d, J = 5.21 Hz, 1 H, pyrid-
C6-H), 7.61 (dd, 1 H, J = 7.32, 8.08 Hz, 1 H,
quin-C7-H), 7.65 (dd, J = 7.32, 8.08 Hz, 1 H,
quin-C6-H), 7.68 (d, J = 8.04 Hz, 1 H, quin-
C5-H), 7.73 (d, J = 8.06 Hz, 1 H, quin-C8-H),
7.87 (s, 1 H, quin-C4-H), 11.90, 12.95 (two s,
2 H, NH, OH, D2O-exchangeable)
4 e
4 f
CH3
2-pyridyl
2-pyridyl
75
42
175–177
170–172
C16H13N3O2
(279.30)
2.37 (s, 3 H, CH3), 7.42–7.63 (m, 6 H, pyrid-
C2,3,4,5-H and quin-C5,6-H), 7.66 (s, 1 H, quin-
C8-H) 7.87 (s, 1 H, quin-C4-H), 11.90, 12.95
(two s, 2 H, NH and OH, D2O-exchangeable)
OCH3
C16H13N3O3
(295.29)
3.32 (s, 3 H, OCH3), 7.73–7.79 (m, 6 H,
pyrid-C2,3,4,5-H and quin-C5,6-H), 7.89 (s, 1 H,
quin-C8-H), 8.78 (s, 1 H, quin-C4-H), 12.31,
13.14 (two s, 2 H, NH and OH, D2O-ex-
changeable)
6 a
H
2-thiazolyl
60
294–296 C13H8ClN3OS 7.30 (dd, J = 7.32, 8.08 Hz, 1 H, quin-C7-H),
(289.74)
7.40 (dd, J = 7.32, 8.08 Hz, 1 H, quin-C6-H),
7.45 (d, J = 4.4 Hz, 1 H, thiaz-C5-H); 7.80 (d,
J = 4.4 Hz, 1 H, thiaz-C4-H), 8.51 (d, J = 8.8
Hz, 1 H, quin-C5-H), 8.72 (d, J = 8.8 Hz, 1 H,
quin-C8-H), 8.94 (s, 1 H, quin-C4-H), 12.10
(s, 1 H, NH, D2O-exchangeable)
6 b
6 c
CH3
2-thiazolyl
2-thiazolyl
72
80
184–186 C14H10ClN3OS 2.36 (s, 3 H, CH3), 7.40 (d, J = 8.8 Hz, 1 H,
(303.77)
quin-C6-H), 7.45 (d, J = 4.62 Hz, 1 H, thiaz-
C5-H), 7.83 (d, J = 4.62 Hz, 1 H, thiaz-C4-H),
8.56 (d, J = 8.8 Hz, 1 H, quin-C5-H), 8.77 (s,
1 H, quin-C8-H), 8.94 (s, 1 H, quin-C4-H),
12.14 (s, 1 H, NH, D2O-exchangeable)
OCH3
227–229 C14H10ClN3O2S 3.63 (s, 3 H, OCH3), overlapping with DMSO,
(319.77)
7.28 (d, J = 8.4 Hz, 1 H, quin-C6-H), 7.35 (d,
J = 4.4 Hz, 1 H, thiaz-C5-H), 7.89 (d, J = 4.4
Hz, 1 H, thiaz-C4-H), 8.51 (d, J = 8.8 Hz,
1 H, quin-C5-H), 8.73 (s, 1 H, quin-C8-H),
8.92 (s, 1 H, quin-C4-H), 12.15 (s, 1 H, NH,
D2O-exchangeable)

Arch. Pharm. Pharm. Med. Chem. 2002, 335, 403–410
Potential Antimicrobial Agents 409
Table 3. (continued)
Comp
No.
R
H
Ar
Yield
[%]
Mp
[°C]
Mol. formula
(Mol. wt.)
1H-NMR
(DMSO-d6)
6 d
2-pyridyl
58
202–204
C15H10ClN3O
(283.71)
6.27, 7.16 (two dd, J = 6.6, 7.32 Hz, 2 H,
pyrid-C4,5-H), 7.23, 7.27 (two d, J = 6.6,
7.32 Hz, 2 H, pyrid-C3,6-H), 7.35 (dd, J =
7.36, 8.08 Hz, 1 H, quin-C7-H), 7.45 (d, J =
8.8 Hz, 1 H, quin-C5-H), 7.60 (dd, J = 7.32,
8.08 Hz, 1 H, quin-C6-H), 7.93 (d, J 7.36 Hz,
1 H, quin-C8-H), 8.43 (s, 1 H, quin-C4-H),
12.78 (s, 1 H, NH, D2O-exchangeable)
6 e
6 f
CH3
2-pyridyl
2-pyridyl
70
55
205–207
C16H12ClN3O
(297.74)
2.35 (s, 3 H, CH3), 7.52–7.73 (m, 4 H, pyrid-
C4,5-H and quin-C5,6-H), 7.83 (s, 1 H, quin-
C8-H), 7.85, 7.91 (two d, J = 6.6 Hz, pyrid-
C3,6-H), 8.47 (s, 1 H, quin-C4-H), 13.10 (s,
1 H, NH, D2O-exchangeable)
OCH3
196–198 C16H12ClN3O2 3.65 (s, 3 H, OCH3), overlapping with DMSO,
(313.74)
7.55–7.71 (m, 4 H, pyrid-C4,5-H and quin-
C5,6-H),7.85 (s, 1 H, quin-C8-H), 7.96 (two d,
J = 5.46 Hz, 2 H, pyrid-C3,6-H), 8.47 (s, 1 H,
quin-C4-H), 12.91 (s, 1 H, NH, D2O-ex-
changeable)
1
Table 4. The physicochemical data and H-NMR of compounds 7 a–f.
Comp
No.
R
H
Yield
[%]
Mp
[°C]
Mol. formula
(Mol. wt.)
1H-NMR
(DMSO-d6)
7 a
7 b
7 c
7 d
7 e
61
60
75
65
70
256–258
>300
C13H7N3OS
(253.28)
7.47 (d, J = 5.21Hz, 1 H, C1-H), 7.60 (d, J = 5.21 Hz, 1 H,
C2-H), 7.78 (dd, J = 7.32, 8.04 Hz, 1 H, C9-H), 8.05 (dd,
J = 7.32, 8.04 Hz, 1 H, C8-H), 8.38 (d, J = 8.04 Hz, 1 H,
C7-H), 8.52 (d, J = 8.8 Hz, 1 H, C10-H), 8.55 (s, 1 H, C6-H).
CH3
OCH3
H
C14H9N3OS
(267.31)
2.43 (s, 3 H, CH3), 6.89 (d, J = 4.4 Hz, 1 H, C1-H), 7.27
(d, J = 4.4 Hz, 1 H, C2-H), 7.54 (d, J = 7.36 Hz, 1 H, C8-
H), 7.91 (d, J = 7.36 Hz, 1 H, C7-H), 8.92 (s, 1 H, C10-H),
8.98 (s, 1 H, C6-H).
175–177
200–202
>300
C14H9N3O2S
(283.31)
3.42 (s, 3 H, OCH3), 7.12 (d, J = 4.2 Hz, 1 H, C1-H), 7.52
(d, J = 4.2 Hz, C2-H), 7.63 (d, J = 8.04 Hz, 1 H, C8-H),
7.96 (d, J = 8.04 Hz, 1 H, C7-H), 8.62 (s, 1 H, C10-H), 8.71
(s, 1 H, C6-H).
C15H9N3O
(247.25)
6.72–7.21 (m, 4 H, C1,2,3,4-H), 7.74 (dd, J = 7.4, 8.2 Hz,
1 H, C10-H), 7.82 (dd, J = 7.4, 8.2 Hz, 1 H, C9-H); 7.91 (d,
J = 7.6 Hz, 1 H, C8-H), 8.46 (d, J = 7.4 Hz, 1 H, C11-H),
8.86 (s, 1 H, C1-H)
CH3
C16H11N3O
(261.28)
2.38 (s, 3 H, CH3), 6.73–7.56 (m, 4 H, C1,2,3,4-H), 7.72 (d, J
= 7.34 Hz, 1 H, C9-H), 7.83 (d, J = 7.34 Hz, 1 H, C8-H),
8.45 (s, 1 H, C11-H), 8.66 (s, 1 H, C7-H)

410 El-Sayed et al.
Arch. Pharm. Pharm. Med. Chem. 2002, 335, 403–410
Table 4. (continued)
Comp
No.
R
Yield
[%]
Mp
[°C]
Mol. formula
(Mol. wt.)
1H-NMR
(DMSO-d6)
7 f
OCH3
50
271–273
C16H11N3O2
(277.28)
3.68 (s, 3 H, OCH3 overlapping with DMSO, 6.82–7.70 (m,
4 H, C1,2,3,4-H), 7.74 (d, J = 8.8 Hz, 1 H, C9-H), 7.78 (d, J
= 8.8 Hz, 1 H, C8-H), 8.44 (s, 1 H, C11-H), 8.66 (s, 1 H,
C7-H)
a The yield is calculated according to Method B.
ed solid was filtered and crystallized from dimethylformamide/
ethanol (1 : 2) to obtain the products 7 a–c and 7 d–f as the
monohydrochlorides. These were treated with 10 N NaOH
(5–10 mL) to give the free bases.IR (cm–1):1666–1660 (C=O).
13C-NMR for 9-methoxythiazolo[3Ј,2Ј:1,2]pyrimido[4,5-b]-
quinolin-5-one 7 c: 166.2 (C5), 160.0 (C3a), 155.5 (C11a), 140.5
(C9), 137.1 (C1), 134.0 (C10a), 130.5 (C5a), 126.6 (C6), 122.0
(C6a), 114.0 (C7), 112.7 (C10), 111.0 (C8), 102.6 (C2), 55.1
(OCH3). 13C-NMR for pyrido [1Ј,2Ј:1,2]pyrimido[4,5-b]quinolin-
6-one 7 d: 163.7 (C6), 158.6 (C4a), 155.2 (C12a), 149.0 (C1),
147.9 (C11a), 142.5 (C6a), 138.0 (C7), 137.6 (C7a), 137.2 (C11),
130.1 (C10), 127.8 (C8), 125.0 (C9), 122.3 (C3), 118.1 (C4),
115.3 (C2). M.S. for thiazolo[3Ј,2Ј:1,2]pyrimido[4,5-b]quinolin-
5-one 7 a m/z %:253 (56 %).229 (10 %), 212 (7 %), 196 (26 %),
186 (100 %), 170 (7 %), 153 (59 %), 142 (18 %), 128 (18 %),
114 (19 %), 100 (12 %), 76 (19 %), 64 (75 %). Physical and
spectral data of the products are recorded in Table 4.
[3] P. C. Appelbaum, P. A. Hunter, J. Antimicrob. Agents 2000,
16, 5–15.
[4] S. Sabatini, V. Cecchetti, O.Tabarrini, A. Fravolini, J. Hete-
rocyclic Chem. 1999, 36, 953–957.
[5] M. Fujita, K. Chiba, J. Nakano,Y.Tominaga, J. Matsumoto,
Chem. Pharm. Bull. 1998, 46, 631–638.
[6] C. S. Cooper, P. L. Klock, D. T. W. Chu, D. J. Hardy, R. N.
Swanson, J. J. Plattner, J. Med. Chem. 1992, 35, 1392–
1398.
[7] D.T.W. Chu, P. B. Fernandes, A. G. Pernet, J. Med. Chem.
1986, 29, 1531–1534.
[8] Yh. Sheu,Y. L. Chen, K. C. Fang, T. C.Wang, C. F. Peng, C.
C. Tzeng, J. Heterocyclic Chem. 1998, 35, 955–964.
[9] H.Koga, A.Itoh, S.Murayama, S.Suzue, T.Irikura, J.Med.
Chem. 1980, 23, 1358–1363.
Antimicrobial activity
[10] J.A.Tucker, V.A.Vail-Lancourt, A.Valerie, J.W.Strohbach,
K. R. Romines, M. E. Schnute, M. M. Cudahy, S. Thais-
rivongs, S. R.Turner, PCT Int. Appl.WO 99 32, 450 Chem.
Abstr. 1999, 131, 73568z.
The microdilution susceptibility test in Muller-Hinton Broth (Ox-
oid) and Sabouraud Liquid Medium (Oxoid) were used for the
determination of antibacterial and antifungal activities [13].
Test organisms included:Staphylococcus aureus ATCC 29213,
Bacillus subtilis ATCC 6633, Bacillus sphaericus; Institute Pas-
teur, Bacillus thuringiensis ATCC 1322, and Bacillus anthracis
as Gram-positive bacteria, Salmonella typhimurium ATCC
3311, Escherichia coli ATCC 25722, and Esherichia coli ATCC
13607 as Gram-negative bacteria, Aspergillus flavus local, as
fungi, and Candida albicans ATCC 10231 as yeast-like fungi.
Ampicillin trihydrate and clotrimazole were used as standard
antibacterial and antifungal agents respectively. Solutions of
the tested compounds, ampicillin trihydrate and clotrimazole,
were prepared in dimethylformamide at a concentration of
1 mg /mL. Two-fold dilution of the compounds was performed.
Plates were incubated at 37 °C for 24 h for bacteria and
48–72 h for fungi. The MICs of all the tested compounds were
determined by means of standard two-fold serial dilution meth-
od using agar media [13]. The results are recorded in Table 1.
[11] O. A. El-Sayed, H. Y. Aboul-Enein, Arch. Pharm. Pharm.
Med. Chem. 2001, 334, 117–120.
[12] O. Meth-Cohn, B. Narine, B. Tarnowski, R. Hayes, A.
Keyzad, S. Rhouati, A. Robinson, J. Chem. Soc. Perkin
Trans. I 1981, 2509–2517.
[13] P. R. Murray, E. J. Baron, M. A. Pfaller, F. C. Tenover, R. H.
Yo l ke n , Manual of Clinical Microbiology, G. L.Woods, J. A.
Washington, Antimicrobial Agents and SusceptibilityTest-
ing, 6th. ed., Am. Soc. Microbiol., Washington, DC, 1995.
[14] O. Meth-Cohn, B. Narine, B. Tarnowski, J. Chem. Soc.
Perkin Trans. I 1981, 15206–1531.
References
[1] Y. L. Chen, K. C. Fang, J.Y. Sheu, S. L. Hsu, C. C.Tzeng, J.
Med. Chem. 2001, 44, 2374–2377.
[2] K. Kawakami, H. Takahashi, H. Ohki, K. Kimura, S. Miya-
uchi, R.Miyauchi, M.Takemura, Chem.Pharm.Bull. 2000,
48, 1667–1672.